The crux of the controversy is data suggesting that use of ACE inhibitors and ARBs may increase expression of ACE2, which leads to the hypothesis that these drugs may increase patient susceptibility to the virus. Several commentaries suggesting that ACE inhibitors and ARBs may increase susceptibility in this way have now appeared.
In one prominent report published as a letter to The Lancet Respiratory Medicine on March 11, Lei Feng, MD, PhD, University Hospital Basel, Switzerland, and colleagues write: "The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs). Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2. ACE2 can also be increased by thiazolidinediones and ibuprofen.
"Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesize that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19," they conclude.
Writing in a Viewpoint in JAMA published online yesterday, Ankit Patel, MD, and Ashish Verma, MBBS, both from Brigham and Women's Hospital, Boston, Massachusetts, give more detailed information on ACE2 expression with ACE inhibitors and ARBs.
"There has been considerable evidence in animal models as well as some evidence in humans showing increased expression of ACE2 in the heart, brain, and even in urine after treatment with ARBs; however, there is limited evidence showing changes in serum or pulmonary ACE2 levels," they write. "More relevant, the significance of ACE2 expression on COVID-19 pathogenesis and mortality is not specifically known."
But even if ACE inhibitors and ARBs do increase ACE2 expression, this does not necessarily mean they increase infectivity of the virus, experts emphasize, and there are also suggestions that an increase in ACE2 may be a positive effect.
In a detailed scientific study in the journal Nephron published March 23, Luca Perico, PhD, Ariela Benigni, PhD, and Guiseppe Remuzzi, MD, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy, say the answer to the question of whether ACE inhibitors and ARBs could predispose patients to increased COVID-19 infection and more severe illness "is not as simple as it seems, at least based on current knowledge."